Nutrient Cocktail for Memory Is Controversial

Action Points

Explain to interested patients that this study suggests that a cocktail of nutrients may improve memory in people with mild Alzheimer's disease.

Caution that many outside experts believe the study did not show a benefit.

A cocktail of nutrients intended to build brain synapses improved memory in a clinical trial of patients with mild Alzheimer's disease, researchers said, but outside experts discounted the study, suggesting its results actually showed no benefit.

The so-called "medical food" improved memory -- at least by one measurement -- in a randomized placebo-controlled trial of 225 patients, according to Philip Scheltens, MD, PhD, of VU University Medical Center in Amsterdam, and colleagues.

But it failed to show an improvement on another measure, regarded as the gold standard for testing Alzheimer's disease treatments, Scheltens and colleagues reported in the January issue of Alzheimer's and Dementia.

Despite that, the researchers argued that the "proof-of-concept study justifies further clinical trials."

Indeed, several such studies are currently under way but the nutrient cocktail is likely to have limited availability to the public even before the results of those trials are known.

According to a corporate press release, the product's maker -- Nutricia Advanced Medical Nutrition -- plans a "small-scale Early Experience Program for consumers" this spring. Nutricia is a subsidiary of Groupe Danone, which sponsored the study.

Such a close corporate link aroused the indignation of one expert, a neurologist at a leading medical school, who called the study "total, utter nonsense."

Clifford B. Saper, MD, PHD, of Harvard, also had reservations about the study. "While everyone would like to have some safe and easy to take method to stave off Alzheimer's disease, there are several features of this study that should raise concerns. They would include the involvement of the commercial sponsors at every level of this study, including writing the first draft of the paper, and the relatively low level of improvement on a single test out of a large battery of examinations," he said in an e-mail.

"All of the tests are set so they have a 1 in 20 chance of giving a false positive answer, so if you do enough of them, the chances of one of them randomly coming up looking positive approaches certainty," he added.

In an e-mail, Scheltens said the trial is "a proof of concept that urges further study, which we are doing." He said the study was indeed analyzed by the sponsor, but also by an external statistician, who is also a co-author of the paper.

Co-author Richard Wurtman, MD, of MIT, said he didn't think the sponsor was overly involved, but added he -- as a basic scientist -- was himself not deeply involved in the clinical aspect of the trial.

Wurtman and colleagues laid the groundwork for the study with animal research showing a synergistic effect of the nucleotide uridine, omega-3 polyunsaturated fatty acids, and choline.

Taken together in animals, those compounds increased brain levels of molecules involved in the formation of synapses and led to an increase in dendritic spines, the precursors of synapses.

The researchers hypothesized that a similar effect in patients with Alzheimer's disease might have clinical benefits. To test the idea, they enrolled 225 patients with mild disease, defined as a score of between 20 and 26 on the Mini-Mental State Examination.

The patients were randomly assigned to take a 125-milliliter tetrapack of the cocktail once a day, at breakfast, or a similarly packaged drink without the active ingredients, the researchers said. The researchers excluded 13 patients excluded from the efficacy analysis, but not the safety analysis, because of a protocol violation.

The primary outcome measures were change after 12 weeks of treatment on the delayed verbal recall test of the Wechsler Memory Scale-revised and the 13-item modified Alzheimer's Disease Assessment Scale-cognitive subscale.

Because about 40% of patients had a score of zero on the Wechsler scale, the researchers used an unplanned statistical model to analyze results over the study period.

Using that nonparametric model to account for the skewed baseline distribution, they found that 40% of patients in the active group showed an improvement on the Wechsler test, compared with 24% in the control group.

The difference reached statistical significance at P=0.026, they reported.

On the other hand, there was no change on the Alzheimer's Disease Assessment Scale.

That discordance led many observers to conclude that the researchers should have reported a negative result.

"Overall, this should be considered a negative study," said Paul Aisen, MD, of the University of California San Diego.

In an e-mail, Aisen cited "a number of serious concerns about the analysis of the results," including the differing results on the two outcome measures.

"When co-primary measures are used, this generally means that both measures must show significant effects for a study to be positive," he said. But even if the data analysis were bullet-proof, he said, a benefit on one scale not matched on the other "would not be considered to be clinically important."

He added that he was concerned that the study was small and of short duration.

MIT's Wurtman countered that the two tests "to some extent measure different things."

In cases of mild disease, he said, it's more likely to get a result on the Wechsler test, which measures just verbal memory, than on the more general Alzheimer's Disease Assessment Scale.

Wurtman added that he thinks it's wrong to insist that both measures should be positive before reporting a positive result.

Norman Foster, MD, of the University of Utah in Salt Lake City, said the study was interesting and "done by highly respected investigators using a state-of-the-art design with adequate provision for overview and statistical analysis."

Despite that, Foster said in an e-mail, the study is "intriguing, but not convincing. I would await a confirmatory study before recommending this treatment."

This article was developed in collaboration with ABC News.

The study was sponsored by Danone Research-Centre for Specialised Nutrition, which is part of Groupe Danone. Design and planning were done in conjunction with the study sponsor, which provided study products. The sponsor undertook data collection and, together with an independent statistician, data analysis.

Scheltens is employed by VU Medical Center, Amsterdam, whose Alzheimer Center receives unrestricted funding from Danone Research. Co-author Richard Wurtman is employed by MIT, which owns patents on uridine, omega-3 fatty acids, and choline to treat brain diseases by enhancing synapses. He is consultant to the Danone Company and advises on research related to such use. Several other authors reported being on the advisory board for Nutricia, a subsidiary of Danone that is developing the tested product.